Project Summary Since the discovery of the Nobel prize-winning mechanism of RNA interference (RNAi) ten years ago, it has become a promising drug target for the treatment of multiple diseases, including cancer. However, significant barriers still exist on the road to clinical applications of siRNA drugs, including poor cellular uptake, instability under physiological conditions, off-target effects and possible immunogenicity. The successful application of siRNA for cancer therapy requires the development of clinically suitable, safe and effective drug delivery systems. We are developing a novel therapeutic strategy for this cancer by harnessing the power of the body?s natural lipoproteins to deliver siRNA specifically to cancer cells that inhibits tumor growth. These siRNA interfere with processes critical to tumorigenesis and metastasis, and offer the potential to reverse poor survival outcomes. Further, inhibition of this gene results in increased tumor apoptosis, which could be leveraged to reduce tumor burden. Here, we present a novel mechanism to deliver the therapeutic siRNA to cancer cells using a reconstituted version of the body?s natural high density lipoprotein (rHDL). This lipoprotein has a long circulating half-life and targets the SR-B1 receptor, which is over-expressed in most types of ovarian cancer cells. Our in vivo experiments demonstrate siRNA/rHDL targets ovarian cancer through the SR-B1 receptor. It also reduces the tumor burden in orthotopic animal models of cancer. The technology has been granted a patent, as well as published in a top-tier peer-reviewed publication. Fannin Partners is a privately held early stage biomedical commercialization company dedicated to the advancement of innovative therapies in early pre-clinical development. The current innovation is the direct result of ground-breaking research conducted by the scientific team of Dr. Andres Lacko and Dr. Anil Sood. Both the original inventors will be directly involved in the development of the drug. The focus of this proposal is to accomplish key milestones that will further transition this cancer therapy technology to commercialization by optimizing manufacturing parameters, measuring distribution to other tissues, metabolism, and elimination, and also give a better understanding of potential toxicities.